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Structure of GSK3β reveals a primed phosphorylation mechanism

Nature Structural Biology volume 8, pages 593–596 (2001)Cite this article

Abstract

GSK3β was identified as the kinase that phosphorylates glycogen synthase but is now known to be involved in multiple signaling pathways. GSK3β prefers prior phosphorylation of its substrates. We present the structure of unphosphorylated GSK3β at 2.7 Å. The orientation of the two domains and positioning of the activation loop of GSK3β are similar to those observed in activated kinases. A phosphate ion held by Arg 96, Arg 180 and Lys 205 occupies the same position as the phosphate group of the phosphothreonine in activated p38γ, CDK2 or ERK2. A loop from a neighboring molecule in the crystal occupies a portion of the substrate binding groove. The structure explains the unique primed phosphorylation mechanism of GSK3β and how GSK3β relies on a phosphoserine in the substrate for the alignment of the β- and α-helical domains.

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Figure 1
Figure 2: The overall structure of GSK3β and comparison with activated substrate-bound CDK2.
Figure 3: Comparison between the activation loops of GSK3β and p38γ.
Figure 4: The GSK3β substrate binding groove.

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References

  1. Kim, L. & Kimmel, A.R. Curr. Opin. Genet. Dev. 10, 508–514 (2000).

    Article  CAS  Google Scholar 

  2. Woodgett, J.R. Semin. Cancer Biol. 5, 269–275 (1994).

    CAS  PubMed  Google Scholar 

  3. Ding, V.W., Chen, R.H. & McCormick, F. J. Biol. Chem. 275, 32475–32481 (2000).

    Article  CAS  Google Scholar 

  4. Summers, S.A. et al. J. Biol. Chem. 274, 17934–17940 (1999).

    Article  CAS  Google Scholar 

  5. Ross, S.E., Erickson, R.L., Hemati, N. & MacDougald, O.A. Mol. Cell Biol. 19, 8433–8441 (1999).

    Article  CAS  Google Scholar 

  6. Waltzer, L. & Bienz, M. Cancer Metastasis Rev. 18, 231–246 (1999).

    Article  CAS  Google Scholar 

  7. Ikeda, S. et al. EMBO. J. 17, 1371–1384 (1998).

    Article  CAS  Google Scholar 

  8. Thomas, G.M. et al. FEBS Lett. 458, 247–251 (1999).

    Article  CAS  Google Scholar 

  9. Salic, A., Lee, E., Mayer, L. & Kirschner, M.W. Mol. Cell 5, 523–532 (2000).

    Article  CAS  Google Scholar 

  10. Hanks, S.K. & Hunter, T. FASEB J. 9, 576–596 (1995).

    Article  CAS  Google Scholar 

  11. Woodgett, J.R. EMBO J. 9, 2431–2438 (1990).

    Article  CAS  Google Scholar 

  12. Hoeflich, K.P. et al. Nature 406, 86–90 (2000).

    Article  CAS  Google Scholar 

  13. Hanks, S.K., Quinn, A.M. & Hunter, T. Science 241, 42–52 (1988).

    Article  CAS  Google Scholar 

  14. Hanks, S.K. & Quinn, A.M. Methods Enzymol. 200, 38–62 (1991).

    Article  CAS  Google Scholar 

  15. Schulze-Gahmen, U. et al. Proteins 22, 378–391 (1995).

    Article  CAS  Google Scholar 

  16. Bellon, S., Fitzgibbon, M.J., Fox, T., Hsiao, H.M. & Wilson, K.P. Structure Fold. Des. 7, 1057–1065 (1999).

    Article  CAS  Google Scholar 

  17. Brown, N.R., Noble, M.E., Endicott, J.A. & Johnson, L.N. Nature Cell Biol. 1, 438–443 (1999).

    Article  CAS  Google Scholar 

  18. Canagarajah, B.J., Khokhlatchev, A., Cobb, M.H. & Goldsmith, E.J. Cell 90, 859–869 (1997).

    Article  CAS  Google Scholar 

  19. Hughes, K., Nikolakaki, E., Plyte, S.E., Totty, N.F. & Woodgett, J.R. EMBO J. 12, 803–808 (1993).

    Article  CAS  Google Scholar 

  20. Woodgett, J.R. & Cohen, P. Biochim. Biophys. Acta 788, 339–347 (1984).

    Article  CAS  Google Scholar 

  21. Kuret, J., Woodgett, J.R. & Cohen, P. Eur. J. Biochem. 151, 39–48 (1985).

    Article  CAS  Google Scholar 

  22. Leslie, A.G.W. Newslett. Protein Crystallogr . 26, 73–80 (1992).

    Google Scholar 

  23. Collaborative Computational Project 4. Acta Cryst. D 50, 760–763 (1994).

  24. Lawrie, A.M. et al. Nature Struct. Biol. 4, 796–801 (1997).

    Article  CAS  Google Scholar 

  25. Navaza, J. Acta Crystallogr. A 50, 157–163 (1994).

    Article  Google Scholar 

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Acknowledgements

We thank K.P. Wilson for his advice, support and help in the preparation of the manuscript, R. Petrillo for protein expression and G. McDermott from Lawrence Berkeley Laboratories for help with data collection. We are grateful to V.L. Sato, J.A. Thomson, M.A. Murcko and M.S.-S. Su for their critical comments on the manuscript.

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  1. Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, 02139-4211, Massachusetts, USA

    Ernst ter Haar, Joyce T. Coll, Douglas A. Austen, Hsun-Mei Hsiao, Lora Swenson & Jugnu Jain

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  1. Ernst ter Haar
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Correspondence to Ernst ter Haar.

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ter Haar, E., Coll, J., Austen, D. et al. Structure of GSK3β reveals a primed phosphorylation mechanism. Nat Struct Mol Biol 8, 593–596 (2001). https://doi.org/10.1038/89624

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